You are here

Article Text

Article menu
Clinical/translational cancer immunotherapy
Original research
Management of infliximab refractory immune checkpoint inhibitor gastrointestinal toxicity: a multicenter case series
  1. Catriona Harvey1,2,
  2. Kazi J Nahar2,3,
  3. Janet McKeown2,3,
  4. Serigne N Lo4,5,
  5. Sheima Farag6,
  6. Nadia Yousaf6,
  7. Kate Young6,
  8. Liselotte Tas7,
  9. Aafke Meerveld-Eggink7,
  10. Christian Blank7,
  11. Austin Thomas8,
  12. Jennifer McQuade9,
  13. Bastian Schilling10,
  14. Douglas B Johnson11,
  15. Roberto Martín Huertas12,
  16. Ana Arance13,
  17. Joanna Lee3,14,
  18. Lisa Zimmer15,
  19. Georgina V Long16,
  20. Matteo S Carlino1,
  21. Yinghong Wang17 and
  22. Alexander Maxwell Menzies2,3
  1. 1Westmead Hospital WNH, Westmead, New South Wales, Australia
  2. 2Melanoma Institute Australia, North Sydney, New South Wales, Australia
  3. 3The University of Sydney, Sydney, New South Wales, Australia
  4. 4Research and Biostatistics Group, Melanoma Institute Australia, North Sydney, New South Wales, Australia
  5. 5Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
  6. 6Royal Marsden Hospital NHS Trust, London, UK
  7. 7Netherlands Cancer Institute, Amsterdam, The Netherlands
  8. 8The University of Texas Health Science Center at Houston, Houston, Texas, USA
  9. 9University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  10. 10Universitatsklinikum Wurzburg, Würzburg, Germany
  11. 11Vanderbilt University Medical Center, Nashville, Tennessee, USA
  12. 12Hospital Clinic de Barcelona, Barcelona, Spain
  13. 13Hospital Clinic and Institut D′Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
  14. 14Westmead Hospital, Westmead, New South Wales, Australia
  15. 15Dermatology, University Hospital Essen, Essen, Germany
  16. 16Melanoma Institute Australia, Wollstonecraft, New South Wales, Australia
  17. 17Gastroenterology, Hepatology & Nutrition, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  1. Correspondence to Dr Alexander Maxwell Menzies; alexander.menzies{at}sydney.edu.au

Abstract

Background Immune checkpoint inhibitor (ICI) gastrointestinal toxicity (gastritis, enteritis, colitis) is a major cause of morbidity and treatment-related death. Guidelines agree steroid-refractory cases warrant infliximab, however best management of infliximab-refractory ICI gastrointestinal toxicity (IRIGItox) is unknown.

Methods We conducted an international multicenter retrospective case series. IRIGItox was defined as failure of symptom resolution ≤grade 1 (Common Terminology Criteria for Adverse Events V.5.0) following ≥2 infliximab doses or failure of symptom resolution ≤grade 2 after one dose. Data were extracted regarding demographics, steroid use, response to treatment, and survival outcomes. Toxicity was graded at symptom onset and time of infliximab failure. Efficacy of infliximab refractory therapy was assessed by symptom resolution, time to resolution and steroid wean duration. Survival outcomes were examined based on immunosuppressive therapy received.

Results 78 patients were identified: median age 60 years; 56% men; majority melanoma (N=70, 90%); 60 (77%) received anti-cytotoxic T-lymphocyte-associated protein 4 alone or in combination with anti-programmed cell death protein-1 and most had colitis (N=74, 95%). 106 post-infliximab treatments were given: 31 calcineurin inhibitors (CNIs); 27 antimetabolites (mycophenolate, azathioprine); 16 non-systemic immunomodulatory agents (eg, mesalazine or budesonide); 15 vedolizumab; 5 other biologics (anti-interleukin-12/23, 16, Janus kinase inhibitors) and 7 interventional procedures (including colectomy); 5 did not receive post-infliximab therapy. Symptom resolution was achieved in most (N=23/31, 74%) patients treated with CNIs; 12/27 (44%) with antimetabolites; 7/16 (44%) with non-systemic immunomodulation, 8/15 (53%) with vedolizumab and 5/7 (71%) with interventional procedures. No non-vedolizumab biologics resulted in toxicity resolution. CNIs had the shortest time to symptom resolution (12 days) and steroid wean (43 days); however, were associated with poorer event-free survival (6.3 months) and overall survival (26.8 months) than other agents. Conversely, vedolizumab had the longest time to toxicity resolution and steroid wean, 66 and 124 days, but most favorable survival data: EFS 24.5 months; median OS not reached. Six death occurred (three due to IRIGItox or management of toxicity; three with persisting IRIGItox and progressive disease).

Conclusions IRIGItox causes major morbidity and mortality. Management is heterogeneous. CNIs appear most likely to result in toxicity resolution in the shortest time period, however, are associated with poorer oncological outcomes in contrast to vedolizumab.

  • Programmed Cell Death 1 Receptor
  • CTLA-4 Antigen
  • Immune Checkpoint Inhibitors
  • Immunotherapy
  • Ipilimumab

Data availability statement

Data are available upon reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2023-008232

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Management of treatment refractory immune-related adverse events is challenging and associated with significant patient morbidity and mortality. Steroid refractory gastrointestinal (GI) toxicity is managed with infliximab; however, best treatment if infliximab fails is unclear.

    WHAT THIS STUDY ADDS

    • This multicenter international case series describes the management of steroid and infliximab refractory GI toxicity in high volume centers with expertize managing immune-related adverse events. Exploratory oncological outcomes by toxicity management are presented.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • This case series will help inform the management of steroid and infliximab refractory GI toxicity and further supports that early recognition of treatment-resistant toxicity to improve patient outcomes.

    Background

    Improved understanding of complex interactions in the tumor microenvironment (TME) and immune checkpoint inhibitors (ICIs) has revolutionized treatment and outcomes for oncology patients with many tumor types, including melanoma. Approved ICIs target immune checkpoint proteins on the surface of cytotoxic T cells: cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)1 2; programmed cell death protein 1 (PD-1)1 and, most recently, lymphocyte-activation gene 3 (LAG-3).3 Manipulation of these proteins or their ligands, as monotherapy or in combination, prevent cancer cells evading cytotoxic or cell-mediated cell death,4 resulting in unparalleled improvements in tumor control and survival.

    The use of ICIs has also led to a specific spectrum of toxicities—termed immune-related adverse events (iRAE). IRAE are distinct from cytotoxic chemotherapy toxicity and generally manageable with dose interruption, treatment cessation, supportive measures, and/or immunomodulation.5 IRAE can affect multiple organ systems—most commonly skin, endocrine, gastrointestinal (GI) tract, liver, and lung.6 GI toxicity (gastritis, enteritis, colitis) is comparatively uncommon in patients treated with PD-1 monotherapy: 22% (3% ≥grade 3), whereas CTLA-4 monotherapy results in diarrhea in 34% of patients (6% ≥grade 3). Combination PD-1/CTLA-4 therapy is associated the highest risk of luminal GI toxicity: 46% (10% ≥grade 3) in the CheckMate 067 trial7 and up to 54% any grade diarrhea in other studies.8 9 GI toxicity is the most frequent severe (grade 3 or higher) iRAE associated with anti-CTLA-4 therapy and is the most common reason for toxicity-associated CTLA-4 discontinuation.8

    Guidelines10–12 agree on first-line management of ICI colitis—namely symptomatic management for mild disease and corticosteroid therapy for persistent or higher-grade cases (oral or intravenous depending on severity). However, some patients either do not respond to high-dose intravenous steroids—primary refractory toxicity—or have a toxicity flare necessitating an increase in the corticosteroid dosage during steroid tapering.13 All guidelines suggest the tumor necrosis factor (TNF)-α inhibitor, infliximab, at a dose of 5–10 mg/kg for steroid refractory disease. The American Society of Clinical Oncology (ASCO) and Society for Immunotherapy of Cancer (SITC) list vedolizumab, an integrin αβ inhibitor, as an alternative option for steroid refractory disease based on two observational studies.14 15 In the event of infliximab refractory disease ASCO suggests consideration of fecal microbiota transplant, Janus kinase (JAK) inhibitor tofacitinib or interleukin (IL)-12 blocking ustekinumab. Other guidelines do not suggest any specific therapeutic options for infliximab refractory disease. Indeed, there is no agreed definition of infliximab refractory GI toxicity. Patients with infliximab refractory toxicity have been shown to have higher grade colitis and longer duration of steroid use compared with steroid and infliximab responsive patients.16

    The purpose of this case series was to establish a definition of infliximab-refractory ICI gastrointestinal toxicity (IRIGItox); estimate incidence; describe patterns of post infliximab toxicity management; estimate their likelihood to result in toxicity resolution; estimate time to toxicity resolution and explore if there was any relationship between post infliximab toxicity management and disease outcomes.

    Methods

    An international multicenter retrospective case series assessing the incidence, investigation, and management of IRIGItox was conducted. IRIGItox was defined as failure of symptom resolution ≤grade 1 (Common Terminology Criteria for Adverse Events (CTCAE) V.5.0) following ≥2 infliximab doses or failure of symptom resolution ≤grade 2 after one dose. This was agreed on as the infliximab dosing for ICI GI toxicity tends to be based on the Food and Drug Administration approved dosing schedule of infliximab for acute severe inflammatory bowel disease17—a dose at 0, 2, and 6 weeks. As such, most patients will have had two doses before exploring other toxicity management. It was important however to capture patients with persisting severe toxicity post only one dose of infliximab who may have alternate immunosuppression expedited, therefore persisting grade 2 toxicity post one dose of infliximab was also included. Cytomegalovirus (CMV) colitis as the primary diagnosis leading to non-responsive GI toxicity was excluded (identified by resolution of symptoms following CMV antiviral therapy or endoscopic CMV detection in luminal biopsy tissue).

    A primary cohort from the Melanoma Institute Australia (MIA) to determine IRIGItox incidence was identified by a search of pharmacy databases to identify all patients who received infliximab for GI toxicity following programmed death-ligand 1 inhibitors, PD-1 inhibitors, CTLA-4 inhibitors as single or combination agents as part of a clinical trial or as standard of care. Individual patient records were screened to identify cases meeting the definition of IRIGItox for further data extraction and used to estimate proportion of IRIGItox among patients treated with infliximab. Patients with any solid organ malignancies and IRIGItox onset January 2013 to February 2021 were then identified at the following centers: MIA (primary cohort); Netherlands Cancer Institute; Royal Marsden Hospital; MD Anderson; University Hospital Würzburg; Vanderbilt University Medical Centre; Hospital Clinic Barcelona; Westmead Hospital and University Hospital, Essen.

    Data were extracted regarding demographics, steroid use, investigations, post infliximab toxicity management, toxicity resolution and survival. Individual patient records were reviewed at contributing centers and data independently quality checked by the lead authors. Eastern Cooperative Oncology Group (ECOG), C-reactive protein (CRP), albumin and fecal calprotectin levels at the time of symptom onset and infliximab failure were included. Cancer diagnosis data includes tumor type, stage, presence or absence of brain metastases, cancer treatment regimen(s), residual toxicity data, response, and survival. For patients with melanoma, melanoma-specific data including American Joint Committee on Cancer stage, eighth edition, lactate dehydrogenase (LDH) and BRAF/NRAS mutation status were extracted. Toxicity was graded (as per CTCAE) at the time of toxicity onset and time of infliximab failure. Time to toxicity onset; time to steroid and infliximab treatment commencement; investigations; post infliximab toxicity management and response were assessed. Duration of steroid wean was calculated as date of initiation of steroid to time of cessation or wean to physiological steroid dose (prednisolone equivalent 5 mg or less).

    The objectives of the study were to: within the primary MIA cohort, estimate the proportion of patients treated with infliximab who had IRIGItox; describe the investigation and management of IRIGItox; assess the efficacy of post infliximab interventions and assess survival data stratified by post infliximab intervention. Resolution of IRIGItox was defined as resolution to ≤CTCAE grade 1 and prednisolone dose ≤5 mg.

    Descriptive statistics have been presented by frequency and percentage for categorical variables and by median (range) and mean (SD) for continuous variables. Toxicity data, including type, CTCAE grade, and steroid treatment were summarized. Time to resolution differences between post infliximab treatment were assessed using t-test. Survival outcomes included overall survival (OS) and event-free survival (EFS) and were analyzed using the Kaplan-Meier method. EFS time was calculated from the date of commencement of first-line treatment in the early or advanced setting to recurrence progressive disease date or death date. OS time was defined as the time span between first-line treatment in the early or advanced setting to date of death. Patients who did not experience any clinical event were censored at their last follow-up date. All survival outcomes were stratified by post infliximab treatment and by resolution of toxicity, respectively. All statistical analyses were performed using R V.4.1.2 (R Core Team, Vienna, Austria) and SAS V.9.4 (SAS Institute). A two-sided p value of <0.05 was considered statistically significant.

    Melanoma Research Database is approved by Sydney Local Health District HREC Protocol No X15-0311 & 2019/ETH06854.

    Results

    Incidence and baseline characteristics

    Within the MIA cohort, 101 patients were identified who received infliximab for ICI GI toxicity, of which 20 (20%) met criteria for IRIGItox. An additional 58 IRIGItox cases were identified from nine centers across six countries (total n=78): Australia (n=21), UK (n=19), the Netherlands (n=20), USA (n=11), Germany (n=5) and Spain (n=2). Baseline demographic characteristics are presented in table 1. The median age was 60 years; 44 (56%) were men, 76 (98%) were ECOG 0 or 1, 70 (90%) had melanoma and 55 (71%) had advanced-stage disease. Sixty (77%) received anti-CTLA-4 (with anti-PD-1 51, single agent 9). The median number of cycles of ICI prior to toxicity onset was 2 (range 1–28). One patient had underlying ulcerative colitis (UC) diagnosed 37 years prior to advanced melanoma diagnosis. The patient’s UC followed a generally indolent course, was stable on long-term low dose sulfasalazine and azathioprine without an acute flare for over a decade prior to initiation of ICI. No increase in immunosuppressant therapy or biologic was initiated prior to ICI as prophylaxis following discussion with gastroenterology.

    View this table:
    Table 1

    Baseline patient demographics and treatment characteristics

    Initial toxicity features

    Toxicity data is presented in table 2. Toxicity occurred early in treatment, after a median of two cycles of immunotherapy. Most patients had colitis (n=74, 95%), ≥grade 3 (n=74, 95%) and required admission for management (n=62, 79%). Median time to steroid initiation was 2.5 days from documented diagnosis of GI toxicity (range 0–50); median maximum steroid dose was 100 mg prednisolone dose equivalent. 46 (59%) patients were primary refractory with no response to steroids. Of the 32 (41%) patients who had rebound toxicity, the median steroid dose at which symptoms flared was 35 mg prednisolone equivalent (range 5–75 mg).

    View this table:
    Table 2

    Pre-infliximab GI toxicity characteristics

    Pre-infliximab investigations were heterogeneous. Twenty-nine (37%) had baseline imaging. Of these, 17 (59%) were abnormal. Forty-six (59%) of patients had a pre-infliximab endoscope with 85% reported as macroscopically abnormal. Of the seven patients with a macroscopically normal endoscopy, four had microscopic abnormalities. The remaining three patients had normal initial endoscopies with clinical features of clinical colitis and subsequent abnormal endoscopies—left-sided macroscopic abnormalities (n=2) or microscopic colitis (n=1). Median time to first infliximab dose from symptom onset was 17.5 days, and patients had a median of two infliximab doses.

    Toxicity features at time of infliximab failure

    Sixty (77%) patients had initial toxicity resolution followed by flare or only partial response to infliximab with ongoing grade ≥2 toxicity. The remaining 18 (23%) patients had no response to infliximab (table 3). At the time of infliximab failure, ECOG and albumin levels both significantly deteriorated from pre-ICI baseline: median ECOG 0 to ECOG 1 (p<0.0001) and median albumin 39 g/L to 30 g/L (p<0.0001) (figure 1). CRP and fecal calprotectin were not significantly different between toxicity onset and time of infliximab failure, CRP 20 versus 18 mg/L p=0.38 and fecal calprotectin 398 versus 473 µg/g of feces p=0.919.

    View this table:
    Table 3

    GI toxicity characteristics at time of infliximab failure

    Figure 1
    Figure 1

    Barplot of ECOG (A) and albumin (B) at onset of toxicity and at infliximab failure. ECOG, Eastern Cooperative Oncology Group.

    Management of infliximab-refractory toxicity

    One hundred and six post infliximab treatments were recorded across 78 patients: 31 calcineurin inhibitors (CNIs) (ciclosporin n=16, tacrolimus n=15); 27 antimetabolites (mycophenolate n=25, azathioprine n=2); 15 vedolizumab; 5 other non-TNF-α biologics (anti IL-12/23 ustekinumab n=3, anti-IL-6 tocilizumab n=1, the JAK inhibitor tofacitinib n=1); 16 non-systemic immunomodulatory (colonic anti-inflammatory, mesalazine n=5, luminal immunosuppression, budesonide n=4, beclomethasone n=7); 7 interventional (surgery n=5, extracorporeal photopheresis (ECP) n=1, fecal microbiota transplantation (FMT) n=1). Five patients did not receive any post infliximab therapy for IRIGItox. Of these, two died of melanoma prior to resolution of toxicity, one died of Escherichia coli bacteremia following bowel perforation secondary to colitis and two ultimately had resolution after multiple (four and six) doses of infliximab over a 3-month period. Multiple post infliximab treatments were required for 23 patents: two post infliximab treatments n=18, three post infliximab treatments n=3 and four post infliximab treatments n=2. The number of patients treated in the adjuvant and neoadjuvant setting in each toxicity management group was similar to the overall study cohort.

    Overall 58 (74%) of patients had toxicity resolution. Of patients who received multiple post infliximab treatments, 18 (78%) achieved toxicity resolution. Toxicity resolution by post infliximab treatment is shown in figure 2A. Resolution was most likely in patients treated with CNIs (n=23/27, 74%); followed by interventional procedures (n=5, 71%) (2/2 total colectomy, 1/3 partial colectomy, 1/1 FMT and 1/1 ECP); vedolizumab 8/15 (53%); antimetabolites (mycophenolate, azathioprine) 12/27 (44%) and non-systemic immunomodulation (mesalazine, budesonide, beclomethasone) 7/16 (44%). None of the five patients treated with non-TNF-α biologics other than vedolizumab achieved toxicity resolution. Rates of toxicity resolution when multiple toxicity management strategies were required were similar for vedolizumab (4/8, 40%) and interventional procedures (3/5, 60%). but lower for CNIs (8/15, 53%) and antimetabolites (3/13, 23%). No non-systemic immunomodulation was successful when multiple post infliximab treatments were required. Of note, in one of the two cases where antimetabolite was recorded as the agent resulting in toxicity resolution when multiple post infliximab treatments were required, it was commenced within 7 days of a CNI and both were continued to after symptom resolution.

    Figure 2
    Figure 2

    (A) Toxicity resolution by post infliximab treatment; (B) For responders, time to resolution and steroid wean (days) by post infliximab treatment. *Compared with vedolizumab, statistically significant shorter time to resolution (p<0.05).

    Time to resolution and duration of steroid dose wean to a physiological dose (≤5 mg) are presented in figure 2B. CNIs had numerically the shortest time to symptom resolution (median 12 days, range 7–35) and steroid wean duration (median 43 days, range 21–67). Vedolizumab therapy was associated with the longest median time to toxicity resolution and time to steroid wean, median 66 (range 52–230) and 124 days (range 74–253), respectively. Compared with vedolizumab, CNIs achieved more rapid toxicity resolution (66 vs 12 days, p<0.001). There was no statistically significant difference between the groups for time to steroid wean ≤5 mg.

    There was a trend to longer time to initiation of vedolizumab and other non-TNF-α biologics compared with other treatments (including CNIs) from initial symptom onset and from first dose of infliximab (online supplemental table 1 and online supplemental figure 1). Compared with those treated with vedolizumab, patients who received a CNI or antimetabolite tended to have slightly lower grade toxicity, but were otherwise largely similar (online supplemental table 1).

    Supplemental material

    Supplemental material

    Survival outcomes

    Of 78 patients, 47 (60%) developed recurrent or progressive disease, exploratory EFS and OS outcomes by post infliximab treatment and toxicity resolution are shown in figure 3A–D. Non-TNF-α biologics other that vedolizumab were associated with the poorest EFS, 3.8 months and OS, 3.8 months. CNIs and no further IRIGItox management were associated with the next poorest EFS (6.3 months and 9.9 months) and OS (26.8 months and 19.7 months, respectively). Median EFS and OS for antimetabolites was 21.8 months and 38.2 months. Median EFS for vedolizumab, non-immunomodulatory therapies and interventional management were 24.5 months, 15.5 months, and 15 months respectively; median OS was not reached for any of these therapies. Compared with patients who achieved toxicity resolution, failure of toxicity resolution was associated with shorter EFS (8.25 vs 15.5 months) and OS (26.8 vs 38.2 months). 37 patients with recurrent or progressive disease underwent further anticancer therapy including 8 courses of radiation, 5 surgical interventions and a total of 29 systemic therapy courses. There were few flares in GI toxicity seen on retreatment—two in patients treated with single agent PD-1 post PD-1/CTLA-4 and two in patients rechallenged with combination PD-1/CTLA-4.

    Figure 3
    Figure 3

    (A) EFS by post infliximab treatment; (B) OS by post infliximab treatment; (C) EFS by toxicity resolution; (D) OS by toxicity resolution. EFS, event-free survival; OS, overall survival; TNF, tumor necrosis factor; MAB, monoclonal antibody.

    A total of six (6%) patients died from toxicity or of progressive disease without resolution of IRIGItox . Patients who died of toxicity or complications of toxicity management include: a patient who developed E. coli sepsis secondary to bowel perforation having received tofacitinib post infliximab; a patient who died of refractory colitis following mycophenolate post infliximab without progressive disease and a patient who died of reactivation of tuberculosis complicating immunosuppression for refractory toxicity—in addition to steroids and infliximab, they received antimetabolites, antivirals and a total colectomy prior to death. Patients who died with both toxicity and progressive disease include: two patients with IRIGItox and progressive disease and a patient in their 30s with progressive melanoma and severe pan-enteritis who died with active toxicity in hospital having received antimetabolites and total parenteral nutrition following infliximab.

    Multivariable analysis

    Univariable and multivariable Cox regression was performed for likelihood of toxicity resolution (online supplemental table 2). Sex, age, steroid refractory subtype, CTLA-4 versus no CTLA-4 regimen and type of post infliximab treatment were included in the model. Treatment center was removed from the model due to small numbers at some sites. In the multivariable analysis, sex and post infliximab treatment were both significantly associated with likelihood of toxicity resolution. Female sex was an independent predictor of toxicity resolution (HR 2.23 (1.17–4.26)) in a more plausible model that accounts for other factors associated with toxicity resolution. Of all the post infliximab toxicity management therapies, ciclosporin was the only treatment significantly associated with toxicity resolution HR 3.29 (1.48–7.33).

    Conclusions

    ICIs have improved survival outcomes across many tumor types; however, GI toxicity occurs frequently and a significant number of patients do not respond to corticosteroid or infliximab treatment. How best to manage infliximab refractory toxicity while retaining antitumour efficacy is unknown. This is the first multicenter case series investigating the incidence, investigation and management of infliximab refractory colitis in patients with cancer pooled from several large centers across six countries. Such a collaborative, multinational cohort has provided a cross-section of practice and has confirmed a heterogeneous approach to IRIGItox.

    Results show the incidence of IRIGItox was in keeping with published infliximab efficacy data in this setting16 18 and confirm that patients deteriorate due to treatment refractory toxicity—both in terms of performance status and albumin level. A multicenter cohort study of 127 patients with corticosteroid refractory ICI colitis19 found that most infliximab responsive patients had clinical response within 7 days of infliximab, suggesting that patients who respond to infliximab will do so quickly, and therefore clinicians should consider alternative agents early should symptoms persist despite infliximab. In our case series, the median time to first post infliximab treatment was 33 days, possibly as a result of a delay in recognition of infliximab refractoriness and/or initiation of post infliximab management. Such delay is likely to have exacerbated deterioration in performance and nutritional status and may have negatively impacted the efficacy of salvage therapies. Similarly, a delay in the initial use of infliximab likely also impacts outcomes (including infliximab responsiveness). Clinicians therefore need to recognize steroid-refractory and infliximab-refractory colitis early, and access other agents before further clinical deterioration.

    Exploratory survival analysis was performed—given small numbers in each post infliximab management group interpretation must be done with caution. CNIs were associated with the highest likelihood of toxicity resolution, most rapid time to resolution and one of the most rapid time to steroid wean; however, EFS and OS show a trend to poorer cancer survival when CNIs were used. This may be explained by their mechanism of action and profound T cell targeted immunosuppression20 leading to enhanced cancer immune escape. Vedolizumab, conversely, was associated with the longest median EFS and median OS was not reached, however, successful symptom resolution was achieved in only 53% of patients and was associated with a prolonged time to symptom resolution (66 days) and steroid wean (124 days). The mechanism of action of vedolizumab is attractive as an organ specific immunosuppressant, however, use in severe cases when rapid symptom resolution is required needs to be approached with caution. Furthermore, translational data suggest that colitis may be driven, at least in part, by expansion of tissue resident immune cells2, such that blocking immune cell trafficking across the gut membrane particularly in well-established/chronic inflammation, may be less effective. As such, vedolizumab needs to be studied in the prophylactic or early-onset setting. Of note there was a statistically non-significant trend toward greater lag from time of colitis onset and first infliximab dose to initiation of vedolizumab when compared with other toxicity management. It may be that this delay in definitive toxicity management negatively impacted the chance of toxicity resolution. The small number of interventional procedures in this case series were associated with a high likelihood of symptom resolution—particularly total colectomy, although with significant morbidity (and little clinical benefit for pan-enteritis). Interestingly, the one FMT and one ECP procedure in this case study both resulted in toxicity resolution—presenting interesting interventions for further study. A Cochrane review21 of the role of FMT in Crohn’s disease and UC has shown fecal transplant may increase rates of induction of clinical remission and endoscopic remission in people with active UC compared with autologous FMT, placebo, mesalamine via enema, the UC Exclusion Diet or ‘routine therapy’ that potentially included mesalamine, corticosteroids, or both. None of the included studies reported data on use of FMT for control of active Crohn’s disease, only in maintenance of remission. A recent case series22 of 12 patients with refractory immune-mediated colitis found that 10 of the 12 patients achieved symptom improvement following FMT and 92% of subjects achieved clinical remission of colitis at the end of the study. All patients included were refractory to steroids and infliximab and/or vedolizumab—similar to our patient population. A published case study23 of ECP used in a patient in their early 20s with multiple iRAEs, including colitis, describes complete clinical and pathological resolution of colitis following two ECP cycles. The patient had previously had no resolution with prolonged steroids, infliximab or ciclosporin. They were able to present data showing normalized macroscopic and histological endoscopy findings; normalized pro inflammatory cytokine markers and expanded natural killer cell populations following ECP treatment.

    Patents who underwent multiple post infliximab treatments were less likely to achieve toxicity resolution with antimetabolites or non-systemic immunomodulation likely reflecting that patients requiring multiple post infliximab treatments have more treatment refractory toxicity and are less likely to respond to comparatively gentle immunosuppression. Interestingly however, among patients needing multiple post infliximab treatments, CNIs were also less likely to result in toxicity resolution compared with when they were the sole post infliximab treatment despite the mechanism of action and profound T-cell suppression. It is postulated that this may be a coding issue and that a combination of treatments or incorrect attribution of the treatment leading to resolution may be a factor. For example, in one case where resolution was attributed to an antimetabolite it commenced within 7 days of the CNI (similar to use of antimetabolites used as steroid sparing agents). Both the antimetabolite and CNI were continued to beyond toxicity resolution. As such, despite documentation during data collection as resolution due to antimetabolite, a combination or delayed response to CNI may be more accurate.

    Patients who failed to achieve toxicity resolution, regardless of post infliximab toxicity management, had a trend to poorer EFS and OS in this case series.

    Most patients included had advanced melanoma, however results are applicable to other solid and hematological malignancy patients with IRIGItox as accepted management of iRAEs is tumor agnostic.10 24 The propensity for melanoma cases is likely due to the relatively high use of anti-CTLA-4—particularly ipilimumab 3 mg/kg, often in combination with anti-PD-1 (nivolumab). It is established that anti-CTLA-4 toxicity is dose dependent25–28 and the use of ipilimumab at a dose of 3 mg/kg in melanoma is more likely to cause severe GI toxicity compared with 1 mg/kg dose used for other indications such as renal cell carcinoma or mesothelioma.

    The definition of toxicity response as CTCAE grade 1 or less is somewhat subjective and may have varied between sites. It is recognized that harder endpoints such as clinical remission and corticosteroid-free remission are more reliable predictors of mucosal healing and sustained remission in conventional inflammatory bowel disease.29 30 No uniform assessment such as endoscopic evaluation or histological confirmation to confirm resolution was required to confirm resolution in the series and is a limitation.

    There was no measurement of anti-infliximab antibodies in this series—development of these antibodies can be associated with shorter duration of response to infliximab in patients with Crohn’s disease31 and develop in up to 61% of patients treated with infliximab. In that trial, they do note that concomitant use of immunosuppression reduced the titer of infliximab antibodies—as such the incidence of antibodies may be lower in our case series as all patients were on systemic corticosteroids at the time of infliximab initiation. However, anti-infliximab antibodies may have been an unidentified reason for apparent TNF-α resistance in some of the patients and alternative humanized TNF-α antibodies such as adalimumab and golimumab may have been effective if explored. The limited size of the sample is also a constraint for regression modeling. However, considering the rarity of infliximab-refractory ICI GI toxicity, international effort was made to acquire the most extensive sample possible.

    In summary, infliximab-refractory ICI GI toxicity is a rare but serious complication of ICI therapy—particularly CTLA-4 containing regimens. Best management likely depends on the clinical scenario; in life threatening cases requiring hospitalization and parenteral nutrition for pan-enteritis, where rapid symptom resolution is essential, CNIs may be considered, acknowledging that they may be associated with poorer cancer outcomes. In cases where there is a more chronic or less severe trajectory, agents such as vedolizumab should be considered.

    Data availability statement

    Data are available upon reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    Ethical approval was granted by the MIA Research Committee and via local institutional protocols by collaborating sites.

    Acknowledgments

    The authors wish to thank the patients and families involved in this study, as well as all staff at Melanoma Institute Australia, Royal Marsden NHS Foundation Trust, the Netherlands Cancer Institute, MD Anderson Cancer Centre, University Hospital Würzburg, Vanderbilt University Medical Centre, Hospital Clinic Barcelona, Westmead and Blacktown Hospitals, University Hospital Essen, and associated institutions. Support from the Cameron family for the Melanoma Institute Australia research database is also gratefully acknowledged. AMM is supported by an NHMRC Investigator Grant, Nicholas and Helen Moore, and Melanoma Institute Australia. GVL is supported by an NHMRC Investigator Grant and the University of Sydney Medical Foundation. SNL is supported by Melanoma Institute Australia.

    References

    1. ↵
      1. Topalian SL,
      2. Drake CG,
      3. Pardoll DM
      . Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015;27:450–61. doi:10.1016/j.ccell.2015.03.001
      OpenUrlCrossRefPubMed
    2. ↵
      1. Nahar KJ,
      2. Marsh-Wakefield F,
      3. Rawson RV, et al
      . Distinct pretreatment innate immune landscape and posttreatment T cell responses underlie immunotherapy-induced colitis. JCI Insight 2022;7:e157839. doi:10.1172/jci.insight.157839
    3. ↵
      1. Maruhashi T,
      2. Sugiura D,
      3. Okazaki I-M, et al
      . LAG-3: from molecular functions to clinical applications. J Immunother Cancer 2020;8:e001014. doi:10.1136/jitc-2020-001014
    4. ↵
      1. Pardoll DM
      . The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252–64. doi:10.1038/nrc3239
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      1. Wang DY,
      2. Salem J-E,
      3. Cohen JV, et al
      . Fatal toxic effects associated with immune checkpoint Inhibitors: a systematic review and meta-analysis. JAMA Oncol 2018;4:1721–8. doi:10.1001/jamaoncol.2018.3923
      OpenUrl
    6. ↵
      1. Postow MA,
      2. Sidlow R,
      3. Hellmann MD
      . Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018;378:158–68. doi:10.1056/NEJMra1703481
      OpenUrlCrossRefPubMed
    7. ↵
      1. Hodi FS,
      2. Chiarion-Sileni V,
      3. Gonzalez R, et al
      . Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol 2018;19:1480–92. doi:10.1016/S1470-2045(18)30700-9
      OpenUrlCrossRefPubMed
    8. ↵
      1. Gupta A,
      2. De Felice KM,
      3. Loftus EV, et al
      . Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther 2015;42:406–17. doi:10.1111/apt.13281
      OpenUrlCrossRefPubMed
    9. ↵
      1. Cabanillas G
      . Immune related adverse events and their treatment in melanoma patients receiving ipilimumab. JCO 2017;35:e14598. doi:10.1200/JCO.2017.35.15_suppl.e14598
    10. ↵
      1. Schneider BJ,
      2. Naidoo J,
      3. Santomasso BD, et al
      . Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol 2021;39:4073–126. doi:10.1200/JCO.21.01440
      OpenUrlCrossRefPubMed
    11. ↵
      1. Haanen J,
      2. Obeid M,
      3. Spain L, et al
      . Management of toxicities from immunotherapy: ESMO clinical practice guideline for diagnosis, treatment and follow-up.
    12. ↵
      1. Brahmer JR,
      2. Abu-Sbeih H,
      3. Ascierto PA, et al
      . Society for immunotherapy of cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer 2021;9:e002435. doi:10.1136/jitc-2021-002435
    13. ↵
      1. Marthey L,
      2. Mateus C,
      3. Mussini C, et al
      . Cancer immunotherapy with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel disease. J Crohns Colitis 2016;10:395–401. doi:10.1093/ecco-jcc/jjv227
      OpenUrlCrossRefPubMed
    14. ↵
      1. Bergqvist V,
      2. Hertervig E,
      3. Gedeon P, et al
      . Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis. Cancer Immunol Immunother 2017;66:581–92. doi:10.1007/s00262-017-1962-6
      OpenUrlCrossRefPubMed
    15. ↵
      1. Zou F,
      2. Faleck D,
      3. Thomas A, et al
      . Efficacy and safety of vedolizumab and infliximab treatment for immune-mediated diarrhea and colitis in patients with cancer: a two-center observational study. J Immunother Cancer 2021;9:e003277. doi:10.1136/jitc-2021-003277
    16. ↵
      1. Nahar KJ,
      2. Rawson RV,
      3. Ahmed T, et al
      . Clinicopathological characteristics and management of colitis with anti-PD1 immunotherapy alone or in combination with ipilimumab. J Immunother Cancer 2020;8:e001488. doi:10.1136/jitc-2020-001488
    17. ↵
      1. Choy MC,
      2. Seah D,
      3. Faleck DM, et al
      . Systematic review and meta-analysis: optimal salvage therapy in acute severe ulcerative colitis. Inflamm Bowel Dis 2019;25:1169–86. doi:10.1093/ibd/izy383
      OpenUrlPubMed
    18. ↵
      1. Ibraheim H,
      2. Baillie S,
      3. Samaan MA, et al
      . Systematic review with meta-analysis: effectiveness of anti-inflammatory therapy in immune checkpoint inhibitor-induced enterocolitis. Aliment Pharmacol Ther 2020;52:1432–52. doi:10.1111/apt.15998
      OpenUrlCrossRefPubMed
    19. ↵
      1. Alexander JL,
      2. Ibraheim H,
      3. Sheth B, et al
      . Clinical outcomes of patients with corticosteroid refractory immune checkpoint inhibitor-induced enterocolitis treated with infliximab. J Immunother Cancer 2021;9:e002742. doi:10.1136/jitc-2021-002742
    20. ↵
      1. Tsuda K,
      2. Yamanaka K,
      3. Kitagawa H, et al
      . Calcineurin inhibitors suppress cytokine production from memory T cells and differentiation of naïve T cells into cytokine-producing mature T cells. PLoS ONE 2012;7:e31465. doi:10.1371/journal.pone.0031465
    21. ↵
      1. Imdad A,
      2. Pandit NG,
      3. Zaman M, et al
      . Fecal transplantation for treatment of inflammatory bowel disease. Cochrane Database Syst Rev 2023;4:CD012774. doi:10.1002/14651858.CD012774.pub3
    22. ↵
      1. Halsey TM,
      2. Thomas AS,
      3. Hayase T, et al
      . Microbiome alteration via fecal microbiota transplantation is effective for refractory immune checkpoint inhibitor-induced colitis. Sci Transl Med 2023;15:eabq4006. doi:10.1126/scitranslmed.abq4006
    23. ↵
      1. Apostolova P,
      2. Unger S,
      3. von Bubnoff D, et al
      . Extracorporeal photopheresis for colitis induced by checkpoint-inhibitor therapy. N Engl J Med 2020;382:294–6. doi:10.1056/NEJMc1912274
      OpenUrl
    24. ↵
      1. Haanen J,
      2. Carbonnel F,
      3. Robert C, et al
      . Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:iv119–42. doi:10.1093/annonc/mdx225
      OpenUrlCrossRefPubMed
    25. ↵
      1. Ascierto PA,
      2. Del Vecchio M,
      3. Mackiewicz A, et al
      . Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma. J Immunother Cancer 2020;8:e000391. doi:10.1136/jitc-2019-000391
    26. ↵
      1. Lebbé C,
      2. Meyer N,
      3. Mortier L, et al
      . Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 trial. J Clin Oncol 2019;37:867–75. doi:10.1200/JCO.18.01998
      OpenUrlPubMed
    27. ↵
      1. Weber JS,
      2. O’Day S,
      3. Urba W, et al
      . Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol 2008;26:5950–6. doi:10.1200/JCO.2008.16.1927
      OpenUrlAbstract/FREE Full Text
    28. ↵
      1. Wolchok JD,
      2. Neyns B,
      3. Linette G, et al
      . Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010;11:155–64. doi:10.1016/S1470-2045(09)70334-1
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      1. Bryant RV,
      2. Winer S,
      3. Travis SPL, et al
      . Systematic review: histological remission in inflammatory bowel disease. Is 'complete' remission the new treatment paradigm? An IOIBD initiative. J Crohns Colitis 2014;8:1582–97. doi:10.1016/j.crohns.2014.08.011
      OpenUrlCrossRefPubMed
    30. ↵
      1. Abreu MT,
      2. Sandborn WJ, IOIBD Defining Endpoints and Biomarkers in Inflammatory Bowel Disease Writing Group
      . Defining endpoints and biomarkers in inflammatory bowel disease: moving the needle through clinical trial design. Gastroenterology 2020;159:2013–8. doi:10.1053/j.gastro.2020.07.064
      OpenUrl
    31. ↵
      1. Baert F,
      2. Noman M,
      3. Vermeire S, et al
      . Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003;348:601–8. doi:10.1056/NEJMoa020888
      OpenUrlCrossRefPubMedWeb of Science

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Twitter @harvey_catriona, @SerineLo, @McQuadeMDLAc

    • Collaborators No collaborator group.

    • Contributors CH and AMM conceived and designed the study. CH, KJN, SF, NY, KY, LT, AM-E, CB, AT, JMQ, BS, DBJ, RMH, AA, JL, LZ, GVL, MSC, YW and AMM collected data. CH, JMK, and SNL analyzed data. CH and AMM wrote the manuscript. CH is acting as guarantor. All the authors revised the manuscript and approved the submission.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests JMQ – Advisory board for BMS, Roche, Merck. AA – Reported honoraria, advisory/consultancy, speaker bureau/expert testimony, travel/accommodation/expenses from Pierre-Fabre, Novartis, MSD, BMS, Amgen, Merck, Sanofi and Eisai Ltd. CB – Reports grants from Advisory role: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures. Research funding: BMS, Novartis, NanoString. Stockownership: Uniti Cars, co-founder Immagene BV, all outside the submitted work. MSC - Advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, Amgen, Ideaya, Merck Serono and Sanofi. DBJ – Advisory boards for Array Biopharma, BMS, Iovance, Jansen, Merck, Novartis, and Oncosec; Receives research grants from BMS and Incyte. GVL - consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma Inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Highlight Therapeutics S.L., Merck Sharp & Dohme, Novartis Pharma AG, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc. AMM – Advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. BS – Honoraria from MSD, BMS, SUN Pharma, Allmiral, Novartis; Advisory Board for MSD, BMS, Pierre Fabre Pharma, Sanofi; travel support from BMS, Novartis, Pierre Fabre Pharma; Research Funding from Novartis; all outside the submitted work. LZ - served as consultant and has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work. KY- support from NIHR RM/ICR Biomedical Research Centre for Cancer, Institutional research support: AVEO Pharmaceuticals, Eisai, Ultimovacs,Teaching/promotional meetings: BMS, Eisai, Ipsen. CH, JL, AM-E, JMK, SNL, LT, KJN, NY, AT, YW and RMH report no disclosures.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.